RESUMO
The European Union (EU) was the first region to establish a regulatory framework for biosimilars, in which animal studies are required to confirm similarity to a reference product. However, animal studies described in European public assessment reports (EPARs) or marketing authorization applications (MAAs) did not identify clinically or toxicologically relevant differences despite differences in quality, suggesting that animal studies lack the sensitivity to confirm biosimilarity. Scientific advice provided learning opportunities to evolve existing guidance. Altogether, the data support a step-wise approach to develop biosimilars that focuses on quality and clinical efficacy of biosimilar. This approach might be more effective and does not necessarily require animal studies, which is also reflected in new EU draft guidance.
Assuntos
Medicamentos Biossimilares/farmacologia , Aprovação de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Medicamentos Biossimilares/normas , Medicamentos Biossimilares/toxicidade , Avaliação Pré-Clínica de Medicamentos/normas , União Europeia , Guias como Assunto , Humanos , Modelos Animais , Controle de Qualidade , Medição de Risco , Especificidade da Espécie , Testes de ToxicidadeRESUMO
The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish the relative immunogenicity of mAbs in NHPs and humans. The incidence of formation of antidrug-antibodies in NHPs and patients was comparable in only 59% of the cases. In addition, the type of antidrug-antibody response was different in NHP and humans in 59% of the cases. Humanization did not necessarily reduce immunogenicity in humans. Immunogenicity interfered with the safety assessment during non-clinical drug development when clearing or neutralizing antibodies were formed. While important to interpret the study results, immunogenicity reduced the quality of NHP data in safety assessment. These findings confirm that the ability to compare relative immunogenicity of mAbs in NHPs and humans is low. Furthermore, immunogenicity limits the value of informative NHP studies.
Assuntos
Anticorpos Monoclonais/imunologia , Formação de Anticorpos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Primatas/imunologia , Animais , Anticorpos Monoclonais/efeitos adversos , Aprovação de Drogas/estatística & dados numéricos , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/estatística & dados numéricos , Indústria Farmacêutica/estatística & dados numéricos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , União Europeia , Humanos , Camundongos , Sistema de Registros/estatística & dados numéricosRESUMO
The value of animal studies to assess drug safety is unclear because many such studies are biased and have methodological shortcomings. We studied whether post-marketing serious adverse reactions to small molecule drugs could have been detected on the basis of animal study data included in drug registration files. Of 93 serious adverse reactions related to 43 small molecule drugs, only 19% were identified in animal studies as a true positive outcome, which suggests that data from animal studies are of limited value to pharmacovigilance activities. Our study shows that drug registration files can be used to study the predictive value of animal studies and that the value of animal studies in all stages of the drug development should be investigated in a collaborative endeavour between regulatory authorities, industry, and academia.
Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Modelos Animais , Sistemas de Notificação de Reações Adversas a Medicamentos , Animais , Humanos , Farmacovigilância , Especificidade da EspécieRESUMO
INTRODUCTION: The first biopharmaceuticals were developed 30 years ago. Biopharmaceuticals differ significantly from small molecule therapeutics (SMTs). Because of such differences, it was expected that classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse effects of biopharmaceuticals. Therefore, until sufficient experience was gained, the preclinical safety evaluation of biopharmaceuticals was carried out on a case-by-case basis. 30 years of experience has since expanded the knowledge base in this area, in the hope to design a preclinical safety evaluation procedure suited to biopharmaceuticals. AREAS COVERED: This review describes how the preclinical safety evaluation of biopharmaceuticals has evolved. It shows that, as result of the risk-averse behavior of regulators and industry, classical procedures were taken as starting point although state-of-the-art knowledge on biopharmaceuticals was directed towards creating a new procedure, driven by the specific properties of biopharmaceuticals. EXPERT OPINION: Current preclinical safety evaluation guidance of biopharmaceuticals is criticized because it employs a checkbox approach. The adverse effects induced by biopharmaceuticals are on-target or immune system-induced, therefore, the preclinical safety evaluation should not be standardized, but rather driven by product specific safety concerns.